In search of potent and selective inhibitors of neuronal nitric oxide synthase with more simple structures |
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| Authors: | Qing Jing Huiying Li Jianguo Fang Linda J Roman Pavel Martásek Thomas L Poulos Richard B Silverman |
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| Institution: | 1. Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA;2. Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA;3. Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA;4. Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA;5. Department of Chemistry, University of California, Irvine, CA 92697-2025, USA;6. Department of Biochemistry, The University of Texas Health Science Center, San Antonio, TX 78384-7760, USA |
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| Abstract: | In certain neurodegenerative diseases damaging levels of nitric oxide (NO) are produced by neuronal nitric oxide synthase (nNOS). It, therefore, is important to develop inhibitors selective for nNOS that do not interfere with other NOS isoforms, especially endothelial NOS (eNOS), which is critical for proper functioning of the cardiovascular system. While we have been successful in developing potent and isoform-selective inhibitors, such as lead compounds 1 and 2, the ease of synthesis and bioavailability have been problematic. Here we describe a new series of compounds including crystal structures of NOS-inhibitor complexes that integrate the advantages of easy synthesis and good biological properties compared to the lead compounds. These results provide the basis for additional structure–activity relationship (SAR) studies to guide further improvement of isozyme selective inhibitors. |
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| Keywords: | Nitric oxide Neuronal nitric oxide synthase Inhibition Aminopyridines |
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